Cardiovascular disease (also called heart disease) is a class of diseases that involve the heart, the blood vessels (arteries, capillaries, and veins) or both. Cardiovascular disease can refer to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease. The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common. Additionally, with aging come a number of physiological and morphological changes that alter cardiovascular function and lead to subsequently increased risk of cardiovascular disease, even in healthy asymptomatic individuals.
Cardiomyopathy refers to diseases of the heart muscle. These diseases have many causes, signs and symptoms, and treatments. In cardiomyopathy, the heart muscle becomes enlarged, thick, or rigid. In rare cases, the muscle tissue in the heart is replaced with scar tissue. As cardiomyopathy worsens, the heart becomes weaker. It is less able to pump blood through the body and maintain a normal electrical rhythm. This can lead to heart failure or irregular heartbeats called arrhythmias. In turn, heart failure can cause fluid to build up in the lungs, ankles, feet, legs, or abdomen. The weakening of the heart also can cause other complications, such as heart valve problems.
The main types of cardiomyopathy are dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular dysplasia. Other types of cardiomyopathy sometimes are referred to as “unclassified cardiomyopathy.” Cardiomyopathy can be acquired or inherited, with hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia substantially being inherited disorders. In some subjects, inherited cardiomyopathies are not evident until the occurrence of a catastrophic event (e.g., heart attack). However, in the absence of some known family history of the inherited cardiomyopathies, general population screening is not practical as diagnosis and monitoring of cardiomyopathy is performed using a combination of medical and family histories, physical examination, blood test, and imaging and functional analyses including chest x-ray, EKG (electrocardiogram), holter and events monitors, echocardiography, stress tests, cardiac catheterization, coronary angiography, myocardial biopsy, and genetic testing.
Cardiomyopathy can be induced by other diseases or conditions, or by various toxins or drugs. For example, dilated cardiomyopathy can result from coronary heart disease, heart attack, high blood pressure, diabetes, thyroid disease, viral hepatitis, and HIV; infections, especially viral infections that inflame the heart muscle can result in cardiomyopathy; alcohol, especially in conjunction with a poor diet; complications during the last month of pregnancy or within 5 months of birth; certain toxins, such as cobalt; and certain drugs (such as cocaine and amphetamines) and chemotherapeutic drugs (e.g., anthracyclines such as doxorubicin and daunorubicin) and drugs for the treatment of diabetes, which can result in abrupt cardiomyopathic events. Restrictive cardiomyopathy can result from conditions such as hemochromatosis, sarcoidosis, amyloidosis, and connective tissue disorders, as well as some cancer treatments, such as radiation and chemotherapy.
Cardiotoxicity is a significant obstacle in the development and approval of drugs. The pharmaceutical industry is currently witnessing a 90% attrition of potential compounds entering clinical development, 30% of which is owing to poor clinical safety (Kola et al. (2004) Nat Rev Drug Discovery: 3 711-715). In the U.S., fatal adverse drug reactions (ADRs) are the 4th to 6th leading causes of death. Costs directly attributable to ADRs may lead to an additional $1.56 to $4 billion in direct hospital costs per year in the U.S. (Lazarou J et al. (1998) JAMA; 279(15):1200-1225). The cost of drug discovery and development has increased to about $1 billion, partly due to increased attrition of compounds and NME late in clinical development (Adams C P, Brantner V V (2010) Spending on New Drug Development. Health Econ. 19: 130-141). The lack of reliable tools that can help with predicting toxicity early in drug development is partly to blame for increasing costs and lower return on investment. Further, drug safety issues are the leading cause of increased litigation and settlements in the pharmaceutical industry. Between January 2009 and May 2011 the industry has spent over $8 billion on litigation cases related to drug safety issues.
In order to augment a “kill early policy” of compounds in early clinical trials and drug development, the FDA is now encouraging the drug industry and the community to adopt a very innovative strategy. FDA white paper Innovation or Stagnation: Challenges and Opportunity on the Critical Path to New Medical Projects states, “A new product development toolkit containing powerful new scientific and technical methods such as animal or computer-based predictive models, biomarkers for safety and effectiveness, and new clinical evaluation techniques—is urgently needed to improve predictability and efficiency along the critical path from laboratory concept to commercial product” (FDA, 2005). The FDA declaration clearly underscores the lack of innovative technologies that can aid in efficient decision making in drug development.
Cardiotoxicity refers to a broad range of adverse effects on heart function induced by agents including therapeutic molecules. Cardiotoxicity may emerge early in pre-clinical studies or become apparent later in the clinical setting. It is a leading cause of drug withdrawal, accounting for over 45% of all drugs withdrawn since 1994, which results in significant financial burden for drug development. Cardiotoxicity results in conditions including increased QT duration, arrhythmias, myocardial ischemia, hypertension and thromboembolic complications, and myocardial dysfunction.
Cardiac safety biomarkers currently used by the FDA include QTc prolongation—lectrophysiological arrhythmias, circulating troponin c, heart rate, blood pressure, lipids, troponin, C-reactive protein (CRP), brain or B-type natriuretic peptide (BNP), ex vivo platelet aggregation, and imaging biomarkers (cardiac magnetic resonance imaging). The QTc prolongation is a very robust but complex marker. However, a decision on whether to kill or sustain a drug in early development is hard to make based on QTc alone. In addition, QTc is subjective and is dependent upon underlying pathologies that can lead to tachyarrythmias.
Accordingly, there is a significant need for new biomarkers for analysis of cardiac safety of drugs and drug candidates, biomarkers for the presence or predisposition in a subject to cardiovascular disease including cardiomyopathy and heart failure.